WASHINGTON, Feb. 5 /PRNewswire-USNewswire/ -- Researchers are
identifying innovative therapeutics for sickle cell anemia that focus on
specific factors in the disease's progression, such as the important role
of hydration of the red blood cells. According to a study prepublished
online in Blood, the official journal of the American Society of
Hematology, a novel small molecule therapy called senicapoc showed efficacy
in maintaining hydration of red blood cells and increasing hemoglobin
levels in patients with sickle cell anemia. Sickle cell anemia affects
about 70,000 Americans, and millions worldwide.

Sickle cell anemia (the most common form of sickle cell disease, or
SCD) is a serious chronic condition in which the red blood cells (RBCs) can
become sickle-shaped upon deoxygenation (shaped like a "C"). Because of
their shape, rigidity, and tendency to stick to blood vessel walls, the
cells do not move easily through the vessels and can form clumps, which may
lead to blocked blood flow and pain, infections, or organ damage. Research
suggests that dehydration of the RBCs is one of the key contributors to the
deformed shape and affects the levels of circulating hemoglobin, an
important determinant of oxygen delivery throughout the body. The
dehydration appears to result from loss of potassium via two pathways, one
of which is known as the Gardos channel. It has been suggested that a
therapy designed to block this channel might have a beneficial effect on
the progression of the disease.

Senicapoc, a known Gardos channel blocker, works by limiting solute and
water loss, thereby preserving RBC hydration. Previous studies have shown
that senicapoc prevents the loss of potassium from the RBCs, is well
tolerated, and has favorable pharmacokinetics with a long half-life,
permitting once-daily dosing.

In a 12-week, multicenter, phase II, randomized, double-blind,
dose-finding study, senicapoc was evaluated for its effect on hemoglobin
level and markers of RBC destruction (hemolysis) in SCD patients. The
investigators also sought to obtain additional safety data and identify the
optimal dose for a phase III study. The primary efficacy endpoint was the
change in blood hemoglobin level from baseline to end of study, and
secondary endpoints included markers of hemolysis, changes in RBC count and
indices, and frequency of painful events or "crises."

"An understanding of the pathophysiology of sickle cell disease is
extremely important in order to identify new therapeutic targets," said
Kenneth Ataga, MD, of the Division of Hematology/Oncology at the University
of North Carolina at Chapel Hill and lead author of the study.

A total of 90 eligible patients were enrolled in the trial. Of these
participants, 24 were also taking hydroxyurea, a drug already approved for
the treatment of SCD. The patients were randomized into three treatment
arms: placebo (n=30), low-dose senicapoc (6 mg/day, n=29), and high-dose
senicapoc (10 mg/day, n=31). Safety and efficacy assessments were obtained
at the end of week one and then every two weeks until completion of the
study treatment.

Patients treated with senicapoc achieved measurable improvements in
hemoglobin levels. Patients in the high-dose senicapoc arm achieved a
hemoglobin increase of 0.68 g/dL (vs. 0.01 g/dL for patients taking
placebo). The team also found corresponding increases in hematocrit and RBC
count in the patients taking senicapoc when compared to placebo. Notably,
the sub-groups of patients taking hydroxyurea achieved similar results. In
the low-dose group, the increase in hemoglobin compared to placebo was not
statistically significant.

Treatment with senicapoc also produced dose-dependent and statistically
significant improvements in secondary endpoints, including the percentage
of dense RBCs (-2.41 vs. -0.08, high-dose vs. placebo), reticulocytes
(-4.12 vs. -0.46), and lactate dehydrogenase (-121 vs. -15), a marker of
hemolysis. There were no differences among the treatment groups in the
overall frequency of painful crises, though crises experiences were
infrequent in this study.

Senicapoc was safe and well tolerated in the study. Ten patients, five
of whom were in the placebo group, discontinued the study early. Three
patients dropped out due to adverse events: one in the low-dose group for
weakness and shortness of breath, and two in the high-dose group for pain
crises and acute chest syndrome. The most common serious adverse effect
(SAE) was pain crisis, followed by pneumonia and acute chest syndrome, with
a similar incidence across the active and placebo arms. None of the SAEs
were thought attributable to senicapoc.

"The results we saw in this study provide further evidence that
blocking the Gardos channel reduces dehydration of the sickle erythrocytes
and thus supports the hypothesis that this type of approach may lead to an
amelioration of the anemic state in patients with sickle cell anemia," said
Dr. Ataga. "As noted in the paper, a Phase III study of senicapoc in SCD
patients was recently terminated due to the low probability of achieving a
reduction in crisis rate, the primary endpoint of that study. Clearly,
further work is necessary to understand how the reduction in RBC
dehydration and hemolysis demonstrated from the results of this Phase II
study impacts the complex pathophysiology of sickle cell disease."

The American Society of Hematology (http://www.hematology.org) is the
world's largest professional society concerned with the causes and
treatment of blood disorders. Its mission is to further the understanding,
diagnosis, treatment, and prevention of disorders affecting blood, bone
marrow, and the immunologic, hemostatic, and vascular systems, by promoting
research, clinical care, education, training, and advocacy in hematology.

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